Cardiac arrhythmias are a major health problem and are associated with very significant morbidity and mortality. There has been an intense interest in the past ca ten years in the nature and treatment of arrhythmias. Currently available antiarrhythmic agents are neither uniformly effective nor well tolerated. The search for new and better antiarrhythmic drugs has produced several promising agents, including mexiletine, flecainide and propafenone. Each of the three agents exists and is used clincially as an equal (racemic) mixture of two optical isomers (enantiomers). Little is known about the pharmacology, toxicity, clinical efficacy, pharmacokinetics and metabolism of the enantiomers, despite increased current awareness that the enantiomers of a chiral drug can differ drastically in their effects and disposition. This application proposes to develop the analytical methodology fundamental to pharmacological, pharmacokinetic and clinical efficacy studies of the enantiomers of mexiletine, flecainide, and propafenone. Specifically, it is proposed (a) to develop chromatographic (HPLC or GLC) methods for the resolution of each racemate for analytical purposes, i.e. determination of enantiomeric purity; (b) to develop HPLC methods for the laboratory (mg)-scale preparative separation of the enantiomers; (c) to develop a chromatography-based simultaneous assay for the two enantiomers of each drug in blood plasma and urine; and (d) to study the intravenous pharmacokinetics of the drugs in rabbits from the stereochemical viewpoint; (e) to examine the general applicability of the methods developed to other chiral drugs of the same chemical class but of a variety of pharmacological classes. Accomplishing these goals will provide the basis for the stereochemical characterization of the actions and disposition of the three drugs, and may lead to better antiarrhythmic agents, e.g., the separate enantiomers. Furthermore, the methods developed may have general applicability to many other chiral drugs.